COCAINE-SENSITIVE SIGMA-RECEPTOR AND ITS INTERACTION WITH STEROID-HORMONES IN THE HUMAN PLACENTAL SYNCYTIOTROPHOBLAST AND IN CHORIOCARCINOMA CELLS

The expression and ligand binding characteristics of sigma-receptors i n human placental syncytiotrophoblast and choriocarcinoma cells were i nvestigated using haloperidol as a ligand. Haloperidol bound to purifi ed placental brush border membranes with high affinity; the apparent d issociation constant for the process was about 3 nM. These binding sit es were not related to dopamine (D-2) and serotonin (5-HT2) receptors nor to serotonin and norepinephrine transporters. The ligands of sigma -receptors e.g.(+)-3-(3-hydroxyphenyl)N-(1-propyl)piperidine, 1,3-di-( 2-tolyl)guanidine, clorgyline, rimcazole, and dexromethorphan] were ve ry potent in competing with haloperidol for the binding sites. The bin ding sites were detected not only in the brush border membrane, but al so in intracellular membranes. The rank order of potency of various si gma-receptor Ligands to inhibit haloperidol binding indicated that pla cental sigma-receptors belong to the 1 sigma subtype. Cocaine and its analog RTI-55 [2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane] inhib ited the binding of haloperidol to placental membranes with appreciabl e potency. The steroid hormones, progesterone and testosterone, were a lso potent inhibitors, and the inhibition constant for progesterone wa s 0.3 mu M, a concentration much smaller than that found in plasma dur ing pregnancy. The inhibition was competitive. beta-Estradiol and a nu mber of other steroids were relatively much weaker inhibitors than pro gesterone and testosterone. Phenytoin and neuropeptide-Y did not inter act with sigma-receptors in placenta. The choriocarcinoma cell line JA R was also found to express sigma-receptors in the plasma membrane as well as in intracellular membranes. The characteristics of the recepto rs in this cell were qualitatively similar to those of the receptors i n normal placenta, including subtype identity and interaction with coc aine and progesterone. Interestingly, however, all sigma-receptor liga nds interacted with the receptors in the JAR cell with much higher aff inity than with the receptors in normal placenta. It is concluded that the placental syncytiotrophoblast and choriocarcinoma cells express c ocaine-sensitive sigma-receptors and that progesterone is most likely an endogenous Ligand for these receptors.